This application is a U.S. National Phase application under 35 U.S.C. xc2xa7371 of PCT Application No. PCT/GB01/02158, filed May 17, 2001, which claims priority under 35 U.S.C. xc2xa7119 from GB Application No. 0012709.2, filed May 24, 2000 and GB Application No. 0107137.2, filed Mar. 24, 2001.
The present invention relates to a class of substituted imidazopyrimidine derivatives and to their use in therapy. More particularly, this invention is concerned with imidazo[1,2-a]pyrimidine analogues which are substituted in the 3-position by a substituted phenyl ring. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six xcex1 subunits, four xcex2 subunits, three xcex3 subunits, one xcex4 subunit, one xcex5 subunit and two xcfx81 subunits.
Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an xcex1 subunit, a xcex2 subunit and a xcex3 subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, xcex4, xcex5 and xcfx81 subunits also exist, but are present only to a minor extent in GABAA receptor populations.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one xcex1, one xcex2 and one xcex3 subunit from a repertoire of seventeen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include, amongst many others, xcex11xcex22xcex32, xcex12xcex2xcex31, xcex12xcex22/3xcex32, xcex13xcex2xcex32/3, xcex14xcex2xcex4, xcex15xcex23xcex32/3, xcex16xcex2xcex32 and xcex16xcex2xcex4. Subtype assemblies containing an xcex11 subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing xcex12 and xcex13 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an xcex15 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat.
A characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the xcex11 subunit in combination with a xcex2 subunit and xcex32. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain.
Two other major populations are the xcex12xcex2xcex32 and xcex13xcex2xcex32/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain xcex15-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.
It is now believed that agents acting as BZ agonists at xcex11xcex2xcex32, xcex12xcex2xcex32 or xcex13xcex2xcex32 subtypes will possess desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as xe2x80x9cGABAA receptor agonistsxe2x80x9d. The xcex11-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAA receptors containing the xcex11 subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the xcex12 and/or xcex13 subunit than with xcex11 will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Moreover, agents which are inverse agonists of the xcex15 subunit are likely to be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer""s disease. Also, agents which are antagonists or inverse agonists at xcex11 might be employed to reverse sedation or hypnosis caused by xcex11 agonists.
The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; speech disorders, including stuttering; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work.
Further disorders for which selective ligands for GABAA receptors may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing disorders, including tinnitus and age-related hearing impairment. Selective ligands for GABAA receptors may be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer""s disease; and may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.
In addition, the compounds in accordance with the present invention may be useful as radioligands in assays for detecting compounds capable of binding to the human GABAA receptor.
The present invention provides a class of imidazo-pyrimidine derivatives which possess desirable binding properties at various GABAA receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the xcex12 and/or xcex13 and/or xcex15 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the xcex12 and/or xcex13 subunit than with the xcex11 subunit; and/or may interact more favourably with the xcex15 subunit than with the xcex11 subunit.
The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the xcex12 and/or xcex13 and/or xcex15 subunit, as measured in the assay described hereinbelow, of 200 nM or less, typically of 100 nM or less, and ideally of 20 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the xcex12 and/or xcex13 and/or xcex15 subunit relative to the xcex11 subunit. However, compounds which are not selective in terms of their binding affinity for the xcex12 and/or xcex13 and/or xcex15 subunit relative to the xcex11 subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of zero or weak (positive or negative) efficacy at the xcex11 subunit and (i) a full or partial agonist profile at the xcex12 and/or xcex13 subunit, and/or (ii) an inverse agonist profile at the xcex15 subunit.
The present invention provides a compound of formula I, or a salt or prodrug thereof: 
wherein
Y represents a chemical bond, an oxygen atom, or a xe2x80x94NHxe2x80x94 linkage;
Z represents an optionally substituted aryl or heteroaryl group;
R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94SO2NRaRb, xe2x80x94NRaRb, xe2x80x94NRaCORb, xe2x80x94NRaCO2Rb, xe2x80x94CORa, xe2x80x94CO2Ra, xe2x80x94CONRaRb or xe2x80x94CRaxe2x95x90NORb; and
Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.
The aryl or heteroaryl group Z in the compounds of formula I above may be unsubstituted, or substituted by one or more substituents. Typically, the group Z will be unsubstituted, or substituted by one or two substituents. Suitably, the group Z is unsubstituted or monosubstituted. Illustrative substituents on the group Z include halogen, cyano, trifluoromethyl, nitro, C1-6 alkoxy, amino, formyl, C2-6 alkoxycarbonyl, methyloxadiazolyl, triazolyl and xe2x80x94CRaxe2x95x90NORb, wherein Ra and Rb are as defined above. Typical substituents on the group Z include halogen, cyano, nitro, amino, formyl, C2-6 alkoxycarbonyl and xe2x80x94CRaxe2x95x90NORb.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The term xe2x80x9chydrocarbonxe2x80x9d as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, indanyl, aryl and aryl(C1-6)alkyl.
The expression xe2x80x9ca heterocyclic groupxe2x80x9d as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl and heteroaryl(C1-6)alkyl groups.
Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as xe2x80x9cC1-6 alkoxyxe2x80x9d, xe2x80x9cC1-6 alkylaminoxe2x80x9d and xe2x80x9cC1-6 alkylsulphonylxe2x80x9d are to be construed accordingly.
Suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl and dimethylallyl groups.
Suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Typical examples of C3-7 cycloalkyl(C1-6)alkyl groups include cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.
Particular indanyl groups include indan-1-yl and indan-2-yl.
Particular aryl groups include phenyl and naphthyl, preferably phenyl.
Particular aryl(C1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.
A typical C3-7 heterocycloalkyl(C1-6)alkyl group is morpholinylmethyl.
Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl, dibenzofrryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The expression xe2x80x9cheteroaryl(C1-6)alkylxe2x80x9d as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl.
The hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from C1-6 alkyl, adamantyl, phenyl, halogen, C1-6 haloalkyl, C1-6 aminoalkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, aryloxy, keto, C1-3 alkylenedioxy, nitro, cyano, carboxy, C2-6 alkoxycarbonyl, C2-6 alkoxycarbonyl(C1-6)alkyl, C2-6 alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C2-6 alkylcarbonyl, arylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, arylsulphonyl, xe2x80x94NRVRW, xe2x80x94NRVCORW, xe2x80x94NRVCO2RW, xe2x80x94NRVSO2RW, xe2x80x94CH2NRVSO2RW, xe2x80x94NHCONRVRW, xe2x80x94CONRVRW, xe2x80x94SO2NRVRW and xe2x80x94CH2SO2NRVRW, in which RV and RW independently represent hydrogen, C1-6 alkyl, aryl or aryl(C1-6)alkyl.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluoro or chloro.
The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
In a preferred embodiment, Y represents a chemical bond.
In another embodiment, Y represents an oxygen atom.
In a further embodiment, Y represents a xe2x80x94NHxe2x80x94 linkage.
Representative values for the substituent Z include phenyl, pyridinyl, thienyl, thiazolyl, imidazolyl and triazolyl, any of which groups may be optionally substituted. Typical values of Z include phenyl, pyridinyl, thienyl and thiazolyl, any of which groups may be optionally substituted. In a favoured embodiment, Z represents an optionally substituted phenyl group, in particular monosubstituted phenyl. In another embodiment, Z represents optionally substituted pyridinyl, especially pyridin-2-yl or pyridin-3-yl.
Examples of suitable substituents on the group Z include fluoro, chloro, cyano, trifluoromethyl, nitro, methoxy, amino, formyl, methoxycarbonyl, methyloxadiazolyl, triazolyl and xe2x80x94CHxe2x95x90NOH. Examples of typical substituents on the group Z include chloro, cyano, nitro, amino, formyl, methoxycarbonyl and xe2x80x94CHxe2x95x90NOH. Examples of particular substituents on the group Z include fluoro, cyano, trifluoromethyl, methoxy, methyloxadiazolyl, triazolyl and xe2x80x94CHxe2x95x90NOH; especially fluoro or cyano; and more especially cyano.
Illustrative values of Z include fluorophenyl, cyanophenyl, (cyano)(fluoro)phenyl, trifluoromethyl-phenyl, nitrophenyl, methoxyphenyl, methyloxadiazolyl-phenyl, triazolyl-phenyl, phenyl-CHxe2x95x90NOH, pyridinyl, (amino)(chloro)pyridiinyl, cyano-pyridinyl, cyano-thienyl, formyl-thienyl, methoxycarbonyl-thienyl, thienyl-CHxe2x95x90NOH, thiazolyl, imidazolyl and triazolyl. Specific values of Z include cyanophenyl, nitrophenyl, pyridinyl, (amino)(chloro)pyridinyl, cyano-thienyl, formyl-thienyl, methoxycarbonyl-thienyl, thienyl-CHxe2x95x90NOH and thiazolyl. Individual values of Z include fluorophenyl, cyanophenyl, (cyano)(fluoro)phenyl, trifluoromethyl-phenyl, methoxyphenyl, methyloxadiazolyl-phenyl, triazolyl-phenyl, phenyl-CHxe2x95x90NOH, pyridinyl, cyano-pyridinyl, thiazolyl, imidazolyl and triazolyl.
A particular value of Z is cyanophenyl, especially 2-cyanophenyl.
Typically, R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, xe2x80x94ORa, xe2x80x94CORa, xe2x80x94CO2Ra or xe2x80x94CRaxe2x95x90NORb. Suitably, R1 represents hydrocarbon, a heterocyclic group, halogen, triiluoromethyl, xe2x80x94ORa, xe2x80x94CORa, xe2x80x94CO2Ra or xe2x80x94CRaxe2x95x90NORb.
Typical values of Ra include hydrogen and C1-6 alkyl. Suitably, Ra represents hydrogen or methyl.
Typical values of Rb include hydrogen, C1-6 alkyl, hydroxy(C1-6)alkyl and di(C1-6)alkylamino(C1-6)alkyl. Suitably, Rb represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of Rb include hydrogen, hydroxyethyl and dimethylaminoethyl, especially hydrogen or dimethylaminoethyl.
Representative values of R1 include hydrogen, C1-6 alkyl, halo(C1-6)alkyl, dihalo(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, di(C1-6)alkoxy(C1-6)alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, C1-6 alkyl-heteroaryl, heteroaryl(C1-6)alkyl, halogen, cyano, trifluoromethyl, C1-6 alkoxy, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl and xe2x80x94CRaxe2x95x90NORb, in which Ra and Rb are as defined above. Typical values of R1 include hydrogen, C1-6 alkyl, halo(C1-6)alkyl, dihalo(C1-6)alkyl, hydroxy(C1-6)alkyl, di(C1-6)alkoxy(C1-6)alkyl, C3-7 cycloalkyl, C37 heterocycloalkyl(C1-6)alkyl, heteroaryl(C1-6)alkyl, cyano, trifluoromethyl, C1-6 alkoxy, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl and xe2x80x94CRaxe2x95x90NORb, in which Ra and Rb are as defined above. Illustrative values of R1 include C1-6 alkyl, hydroxy(C1-6)alkyl, heteroaryl, halogen, triiluoromethyl, C1-6 alkoxy, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl and xe2x80x94CRaxe2x95x90NORb, in which Ra and Rb are as defined above.
Itemised values of R1 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially 1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and xe2x80x94CR2xe2x95x90NOR3, in which R2 represents hydrogen or methyl, and R3 represents hydrogen, hydroxyethyl or dimethylaminoethyl.
Selected values of R1 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, triazolylmethyl, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and xe2x80x94CR2xe2x95x90NOR3, in which R2 and R3 are as defined above.
Individual values of R1 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, triazolylmethyl, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and xe2x80x94CR2xe2x95x90NOR3, in which R2 and R3 are as defined above.
Specific values of R1 include methyl, hydroxymethyl, hydroxyethyl, furyl, chloro, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and xe2x80x94CR2xe2x95x90NOR3, in which R2 and R3 are as defined above.
A particular value of R1 is C1-6 alkyl, especially methyl.
In one favoured embodiment, R1 represents 2-hydroxyprop-2-yl. In another favoured embodiment, R1 represents trifluoromethyl.
Suitably, R2 is hydrogen.
Suitably, R3 represents hydrogen or dimethylaminoethyl, especially hydrogen.
A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof: 
wherein
Z is as defined above;
R11 represents hydrogen, C1-6 alkyl, halo(C1-6)allyl, dihalo(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, di(C1-6)alkoxy(C1-6)alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, C1-6 alkylheteroaryl, heteroaryl(C1-6)alkyl, halogen, cyano, trifluoromethyl, C1-6 alkoxy, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl or xe2x80x94CR4xe2x95x90NOR5;
R4 represents hydrogen or C1-6 alkyl; and
R5 represents hydrogen, C1-6 alkyl, hydroxy(C1-6)alkyl or di(C1-6)alkylamino((C1-6)alkyl.
The present invention also provides a compound of formula IIA as depicted above, or a salt or prodrug thereof, wherein
R11 represents C1-6 alkyl, hydroxy(C1-6)alkyl, heteroaryl, halogen, trifluoromethyl, C1-6 alkoxy, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl or xe2x80x94CR4xe2x95x90NOR5; and
Z, R4 and R5 are as defined above.
Suitably, R4 represents hydrogen or methyl, especially hydrogen.
Suitably, R5 represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R5 include hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, R5 represents hydrogen or dimethylaminoethyl, especially hydrogen.
Where R11 represents C3-7 heterocycloalkyl(C1-6)alkyl, this group is suitably morpholinylmethyl.
Where R11 represents heteroaryl, this group is suitably pyridinyl, furyl, thienyl or oxazolyl, especially furyl.
Where R11 represents C1-6 alkyl-heteroaryl, this group is suitably methylthiazolyl (e.g. 2-methylthiazol-5-yl) or methyloxadiazolyl (e.g. 3-methyl-[1,2,4]oxadiazol-5-yl).
Where R11 represents heteroaryl(C1-6)alkyl, this group is suitably imidazolylmethyl or triazolylmethyl.
Typical values of R11 include hydrogen, C1-6 alkyl, halo(C1-6)alkyl, dihalo(C1-6)alkyl, hydroxy(C1-6)alkyl, di(C1-6)alkoxy(C1-6)alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl(C1-6)alkyl, cyano, trifluoromethyl, C1-6 alkoxy, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl and xe2x80x94CR4xe2x95x90NOR5, in which R4 and R5 are as defined above.
Itemised values of R11 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially 1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and xe2x80x94CR2xe2x95x90NOR3, in which R2 and R3 are as defined above.
Selected values of R11 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, triazolylmethyl, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and xe2x80x94CR2xe2x95x90NOR3, in which R2 and R3 are as defined above.
Individual values of R11 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, dimethoxymethyl, dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, tert-butyl, cyclopropyl, cyclobutyl, morpholinylmethyl, triazolylmethyl, cyano, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and xe2x80x94CR2xe2x95x90NOR3, in which R2 and R3 are as defined above.
Representative values of R11 include methyl, hydroxymethyl, hydroxyethyl, furyl, chloro, trifluoromethyl, methoxy, formyl, acetyl, methoxycarbonyl and xe2x80x94CR2xe2x95x90NOR3, in which R2 and R3 are as defined above.
A particular value of R11 is C1-6 alkyl, especially methyl.
In one favoured embodiment, R11 represents 2-hydroxyprop-2-yl. In another favoured embodiment, R11 represents trifluoromethyl.
One representative subset of the compounds of formula IIA above is represented by the compounds of formula IIB, and salts and prodrugs thereof: 
wherein Z is as defined above.
Another representative subset of the compounds of formula IIA above is represented by the compounds of formula IIC, and salts and prodrugs thereof: 
wherein
X represents CH or N;
R6 represents fluoro, cyano, trifluoromethyl, methoxy, methyloxadiazolyl, triazolyl or xe2x80x94CR2xe2x95x90NOR3;
R7 represents hydrogen or fluoro; and
R2, R3 and R11 are as defined above.
In a favoured embodiment, X represents CH. In another embodiment, X represents N.
In a particular embodiment, R6 represents cyano.
In one embodiment, R7 is hydrogen. In another embodiment, R7 is fluoro.
In a specific embodiment of the compounds of formula IIC, X is CH, R6 is cyano, and R7 is hydrogen.
A further representative subset of the compounds of formula IIA above is represented by the compounds of formula IID, and salts and prodrugs thereof: 
wherein
W represents CH or N; and
R11 is as defined above.
In one embodiment, W represents CH. In another embodiment, W represents N.
In relation to formula IID above, the substituent R11 favourably represents trifluoromethyl.
Specific compounds within the scope of the present invention include:
3xe2x80x2-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(imidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-[7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile;
3xe2x80x2-(7-acetylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-isopropylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-cyclopropylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-tert-butylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-cyclobutylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-methoxyimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-fluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-formylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-(7-hydroxyiminomethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3-(2xe2x80x2-cyanobiphenyl-3-yl)imidazo[1,2-a]pyrimidine-7-carbonitrile;
3-(2xe2x80x2-methoxybiphenyl-3-yl)-7-methylimidazo[1,2-a]pyrimidine;
3-(2xe2x80x2-cyanobiphenyl-3-yl)imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester;
3xe2x80x2-(7-dimethoxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3xe2x80x2-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile;
3xe2x80x2-(7-difluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
7-methyl-3-[3-(pyridin-3-yl)phenyl]imidazo[1,2-a]pyrimidine;
7-methyl-3-[3xe2x80x2-(5-methyl-[1,2,4]oxadiazol-3-yl)biphenyl-3-yl]imidazo[1,2-a]pyrimidine;
7-methyl-3-[2xe2x80x2-(3-methyl-[1,2,4]oxadiazol-5-yl)biphenyl-3-yl]imidazo[1,2-a]pyrimidine;
7-methyl-3-[3-(thiazol-4-yl)phenyl]imidazo[1,2-a]pyrimidine;
3xe2x80x2-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbaldehyde oxime;
3-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]pyridine-2-carbonitrile;
7-methyl-3-[3-(pyridin-2-yl)phenyl]imidazo[1,2-a]pyrimidine;
7-methyl-3-[3-(thiazol-2-yl)phenyl]imidazo[1,2-a]pyrimidine;
7-methyl-3-(2xe2x80x2-trifluoromethylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine;
3-(2xe2x80x2-fluorobiphenyl-3-yl)-7-methylimidazo[1,2-a]pyrimidine;
4-fluoro-3xe2x80x2-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
3-[3-(imidazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;
3-[3-([1,2,4]triazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;
3-[2xe2x80x2-([1,2,4]triazol-1-yl)biphenyl-3-yl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;
3xe2x80x2-[7-(morpholin-4-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile;
4-fluoro-3xe2x80x2-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile;
4-fluoro-3xe2x80x2-[7-(2-hydroxyprop-2-yl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile;
3-[3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;
3-[3-([1,2,4]triazol-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine;
and salts and prodrugs thereof.
Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof.
Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The binding affinity (Ki) of the compounds according to the present invention for the xcex13 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The xcex13 subunit binding affinity (Ki) of the anxiolytic compounds of the invention is ideally 50 nM or less, preferably 10 nM or less, and more preferably 5 nM or less.
The anxiolytic compounds according to the present invention will ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the xcex13 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the xcex11 subunit of the human GABAA receptor.
The potentiation of the GABA EC20 response in stably transfected cell lines expressing the xcex13 and xcex11 subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al., Mol. Pharmacol., 1996, 50, 670-678. The procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltkxe2x88x92 fibroblast cells.
The compounds according to the present invention may exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are likely to be substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al., J. Psychopharmacol., 1996, 10, 206-213).
The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501.
In another aspect, the present invention provides a method for the treatment and/or prevention of cognitive disorders, including dementing conditions such as Alzheimer""s disease, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
Cognition enhancement can be shown by testing the compounds in the Morris watermaze as reported by McNamara and Skelton, Psychobiology, 1993, 21, 101-108. Further details of relevant methodology are described in WO 96/25948.
Cognitive disorders for which the compounds of the present invention may be of benefit include delirium, dementia, amnestic disorders, and cognition deficits, including age-related memory deficits, due to traumatic injury, stroke, Parkinson""s disease and Down Syndrome. Any of these conditions may be attributable to substance abuse or withdrawal. Examples of dementia include dementia of the Alzheimer""s type with early or late onset, and vascular dementia, any of which may be uncomplicated or accompanied by delirium, delusions or depressed mood; and dementia due to HIV disease, head trauma, Parkinson""s disease or Creutzfeld-Jakob disease.
In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called xe2x80x9cblood-brain barrierxe2x80x9d. Preferably, the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of neurological disorders, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
The compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV: 
wherein Y, Z and R1 are as defined above, L1 represents a suitable leaving group, and M1 represents a boronic acid moiety xe2x80x94B(OH)2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol, or M1 represents xe2x80x94Sn(Alk)3 in which Alk represents a C1-6 alkyl group, typically n-butyl; in the presence of a transition metal catalyst.
The leaving group L1 is typically a halogen atom, e.g. bromo.
The transition metal catalyst of use in the reaction between compounds III and IV is suitably tetrakis(triphenylphosphine)-palladium(0). The reaction is conveniently carried out at an elevated temperature in a solvent such as N,N-dimethylacetamide, 1,4-dioxane or tetrahydrofuran, advantageously in the presence of potassium phosphate, copper(I) iodide or sodium carbonate. Alternatively, the transition metal catalyst employed may be dichloro[1,1xe2x80x2-bis(diphenylphosphino)-ferrocene]palladium(II), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as N,N-dimethylformamide.
In an alternative procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula V with a compound of formula VI: 
wherein Y, Z, R1, L1 and M1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
In another procedure, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula VII with a compound of formula VIII: 
wherein Z, R1, L1 and M1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
In the compounds of formula VII above, the leaving group L1 is typically trifluoromethanesulfonyloxy (triilyloxy); or a halogen atom, e.g. bromo.
Alternatively, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula IX with a compound of formula X: 
wherein Z, R1, L1 and M1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
In an additional procedure, the compounds according to the present invention in which Y represents an oxygen atom may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XI: 
wherein R1 is as defined above.
The reaction is conveniently carried out under basic conditions, e.g. using sodium hydride in a solvent such as N,N-dimethylformamide, typically at an elevated temperature which may be in the region of 120xc2x0 C.
In a further procedure, the compounds according to the present invention in which Y represents a xe2x80x94NHxe2x80x94 linkage may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XII: 
wherein R1 is as defined above.
In relation to the reaction between compounds X and XII, the leaving group L1 in the compounds of formula X may suitably represent fluoro.
The reaction between compounds X and XII is conveniently carried out by heating the reactants, typically at a temperature in the region of 120xc2x0 C., in a solvent such as N,N-dimethylformamide.
Where M1 in the intermediates of formula IV and IX above represents a cyclic ester of a boronic acid moiety xe2x80x94B(OH)2 formed with pinacol or neopentyl glycol, the relevant compound IV or IX may be prepared by reacting bis(pinacolato)diboron or bis(neopentyl glycolato)diborane respectively with a compound of formula VIA or VIIA: 
wherein Y, Z and R1 are as defined above, and L2 represents hydroxy or a suitable leaving group; in the presence of a transition metal catalyst.
Where L2 represents a leaving group, this is typically triflyloxy; or a halogen atom such as bromo.
The transition metal catalyst of use in the reaction between bis(pinacolato)diboron or bis(neopentyl glycolato)diborane and compound VIA or VIIA is suitably dichloro[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]-palladium(II). The reaction is conveniently carried out at an elevated temperature in a solvent such as 1,4-dioxane, optionally in admixture with dimethylsulfoxide, typically in the presence of 1,1xe2x80x2-bis(diphenylphosphino)ferrocene and/or potassium acetate.
Where L1/L2 in the intermediates of formula VII/VIIA above represents triflyloxy, the relevant compound VII/VIIA may be prepared by reacting the appropriate compound of formula XI as defined above with triflic anhydride, typically in the presence of pyridine. Analogous conditions may be utilised for converting an intermediate of formula VIA above wherein L2 represents hydroxy into the corresponding compound of formula VI/VIA wherein L1/L2 represents triflyloxy.
The intermediates of formula XI above may suitably be prepared from the appropriate methoxy-substituted precursor of formula XIII: 
wherein R1 is as defined above; by treatment with hydrogen bromide, typically in acetic acid at reflux.
The intermediates of formula XII and XIII above may be prepared by reacting a compound of formula III as defined above with the appropriate compound of formula XV: 
wherein M1 is as defined above, and Y1 represents amino or methoxy; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. In particular, the transition metal catalyst of use in the reaction between compounds III and XIV is suitably tetrakis(triphenylphosphine)-palladium(0), in which case the reaction is conveniently carried out at an elevated temperature in a solvent such as aqueous 1,2-dimethoxyethane, advantageously in the presence of sodium carbonate.
Where M1 in the intermediates of formula V above represents xe2x80x94Sn(Alk)3 and Alk is as defined above, this compound may be prepared by reacting a compound of formula III as defined above with a reagent of formula (Alk)3Snxe2x80x94Hal, in which Hal represents a halogen atom, typically chloro. The reaction is conveniently effected by treating compound III with isopropylmagnesium chloride, typically in a solvent such as tetrahydrofuran, with subsequent addition of the stannyl reagent (Alk)3Snxe2x80x94Hal.
Where L1 in the intermediates of formula III above represents bromo, this compound may be prepared by bromination of the corresponding compound of formula XV: 
wherein R1 is as defined above; typically by treatment with bromine in methanol, in the presence of sodium acetate and optionally also potassium bromide.
The intermediates of formula XV may be prepared by reacting chloroacetaldehyde or bromoacetaldehyde, or an acetal derivative thereof, e.g. the dimethyl or diethyl acetal thereof, with the requisite compound of formula XVI: 
wherein R1 is as defined above.
Where chloroacetaldehyde or bromoacetaldehyde is utilised as one of the reactants, the reaction is conveniently carried out by heating the reactants under basic conditions in a suitable solvent, e.g. sodium methoxide or sodium hydrogencarbonate in a lower alkanol such as methanol and/or ethanol at the reflux temperature of the solvent. Where an acetal derivative of chloroacetaldehyde or bromoacetaldehyde, e.g. the dimethyl or diethyl acetal thereof, is utilised as one of the reactants, the reaction is conveniently effected by heating the reactants under acidic conditions in a suitable solvent, e.g. aqueous hydrobromic acid in a lower alkanol such as methanol or ethanol, typically at the reflux temperature of the solvent.
In a still further procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula XVI as defined above with a compound of formula XVII: 
wherein Y and Z are as defined above, and L3 represents a suitable leaving group; under conditions analogous to those described above for the reaction between chloroacetaldehyde or bromoacetaldehyde, or an acetal derivative thereof, and compound XVI.
The leaving group L3 is suitably a halogen atom, e.g. bromo.
The intermediates of formula XV may also be prepared by reacting a compound of formula XVIII or XIX with the compound of formula XX, or with an acid addition salt of the latter compound, e.g. the hemnisulfate salt: 
wherein R1 is as defined above, and Alk1 represents C1-6 alkyl.
Typical values of Alk1 include methyl and ethyl.
The reaction is conveniently effected by heating the reactants under basic conditions in a suitable solvent , e.g. a lower alkoxide such as sodium methoxide or ethoxide in a lower alkanol such as methanol or ethanol, typically at the reflux temperature of the solvent.
In a yet further procedure, the compounds according to the present invention wherein R1 represents an aryl or heteroaryl moiety may be prepared by a process which comprises reacting a compound of formula XXI with a compound of formula XXII: 
wherein Y, Z and M1 are as defined above, R1a represents an aryl or heteroaryl moiety, and L4 represents a suitable leaving group; in the presence of a transition metal catalyst.
The leaving group L4 is typically a halogen atom, e.g. chloro.
The transition metal catalyst of use in the reaction between compounds XXI and XXII is suitably tetrakis(triphenylphosphine)-palladium(0), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as N,N-dimethylacetamide, typically in the presence of potassium phosphate or in the presence of lithium chloride and copper(I) iodide. Alternatively, the transition metal catalyst may suitably be tris(dibenzylideneacetone)palladium(0), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of tri-tert-butylphosphine and cesium carbonate.
Where L4 in the compounds of formula XXI above represents a halogen atom, these compounds correspond to compounds of formula I as defined above wherein R1 represents halogen, and they may therefore be prepared by any of the methods described above for the preparation of the compounds according to the invention.
The compound of formula XX above is commercially available from the Sigma-Aldrich Company Ltd., Dorset, United Kingdom.
Where they are not commercially available, the starting materials of formula VI, VIII, X, XIV, XVI, XVII, XVIII, XIX and XXI may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. For example, a compound of formula I wherein R1 represents xe2x80x94C(Oxe2x80x94Alk1)2Ra initially obtained, wherein Alk1 is as defined above, may be converted into the corresponding compound of formula I wherein R1 represents xe2x80x94CORa by hydrolysis with a mineral acid, typically aqueous hydrochloric acid. A compound wherein R1 represents formyl may be reduced with sodium triacetoxyborohydride to the corresponding compound wherein R1 represents hydroxymethyl. A compound of formula I wherein R1 represents hydroxymethyl may be oxidised to the corresponding compound of formula I wherein R1 represents formyl by treatment with manganese dioxide. The formyl derivative thereby obtained may be condensed with a hydroxylamine derivative of formula H2Nxe2x80x94ORb to provide a compound of formula I wherein R1 represents xe2x80x94CHxe2x95x90NORb. Furthermore, a compound of formula I wherein R1 represents xe2x80x94CHxe2x95x90NOH may be treated with triethylamine in the presence of 1,1xe2x80x2-carbonyldiimidazole to afford a corresponding compound of formula I wherein R1 represents cyano. Alternatively, the compound of formula I wherein R1 represents formyl may be reacted with a Grignard reagent of formula RaMgBr to afford a compound of formula I wherein R1 represents xe2x80x94CH(OH)Ra, and this compound may in turn be oxidised using manganese dioxide to the corresponding compound of formula I wherein R1 represents xe2x80x94CORa. The latter compound may then be condensed with a hydroxylamine derivative of formula H2Nxe2x80x94ORb to provide a compound of formula I wherein R1 represents xe2x80x94CRaxe2x95x90NORb. A compound of formula I wherein R1 represents xe2x80x94CH(OH)Ra may be converted into the corresponding compound of formula I wherein R1 represents xe2x80x94CHFRa by treatment with (diethylamino)sulfur trifluoride (DAST). Similarly, a compound of formula I wherein R1 represents xe2x80x94CORa may be converted into the corresponding compound of formula I wherein R1 represents xe2x80x94CF2Ra by treatment with DAST. A compound of formula I wherein R1 represents amino may be converted into the corresponding compound of formula I wherein R1 represents chloro by diazotisation, using sodium nitrite, followed by treatment with copper(I) chloride. A compound of formula I wherein R1 represents xe2x80x94COCH3 may be treated with thioacetamide in the presence of pyridinium tribromide to furnish the corresponding compound of formula I wherein R1 represents 2-methylthiazol-5-yl. Moreover, a compound of formula I wherein R1 is formyl may be treated with (p-tolylsulfonyl)methyl isocyanide (TosMIC) in the presence of potassium carbonate to afford the corresponding compound of formula I wherein R1 represents oxazol-5-yl. A compound of formula I wherein R1 represents hydroxymethyl may be treated with carbon tetrabromide and triphenylphosphine to afford the corresponding compound of formula I wherein R1 represents bromomethyl, which may then be reacted (typically in situ) with the sodium salt of imidazole or 1H-[1,2,4]triazole to provide a compound of formula I wherein R1 represents imidazol-1-ylmethyl or [1,2,4]triazol-1-ylmethyl respectively; or with the sodium salt of 1H-[1,2,3]triazole to provide a mixture of compounds of formula I wherein R1 represents [1,2,3]triazol-1-ylmethyl and [1,2,3]triazol-2-ylmethyl; or with morpholine to provide a compound of formula I wherein R1 represents morpholin-4-ylmethyl.
Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following Examples illustrate the preparation of compounds according to the invention.
The compounds in accordance with this invention potently inhibit the binding of [3H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the xcex12 and/or xcex13 and/or xcex15 subunit stably expressed in Ltkxe2x88x92 cells.
Phosphate buffered saline (PBS).
Assay buffer: 10 mM KH2PO4, 100 mM KCl, pH 7.4 at room temperature.
[3H]-Flumazenil (18 nM for xcex11xcex23xcex32 cells; 18 nM for xcex12xcex23xcex32 cells; 10 nM for xcex13xcex23xcex32 cells; 10 nM for xcex15xcex23xcex32 cells) in assay buffer.
Flunitrazepam 100 xcexcM in assay buffer.
Cells resuspended in assay buffer (1 tray to 10 ml).
Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cmxc3x9725 cm) of cells.
Can be carried out in deep 96-well plates or in tubes. Each tube contains:
300 xcexcl of assay buffer.
50 xcexcl of [3H]-flumazenil (final concentration for xcex11xcex23xcex32: 1.8 nM; for xcex12xcex23xcex32: 1.8 nM; for xcex13xcex23xcex32: 1.0 nM; for xcex15xcex23xcex32: 1.0 nM).
50 xcexcl of buffer or solvent carrier (e.g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to determine non-specific binding), 10 xcexcM final concentration.
100 xcexcl of cells.
Assays are incubated for 1 hour at 40xc2x0 C., then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3xc3x973 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be calculated for each test compound.